Hormones have largely been overlooked as regulators of primary B cell development in the bone marrow. However, a new finding from this laboratory showing that suppressed B cell production in thyroid hormone deficient mice can be corrected by thyroxine treatment indicates the importance of the pituitary/thyroid axis to normal B lymphopoiesis. The goal of this proposal is to define the mechanism(s) by which thyroid hormones regulate B lymphopoiesis and to identify additional hormones required for that process. Aim 1 will investigate the biology of thyroid hormone actions on B cell development and function in vivo by examining their effects in both normal and hormonally deficient mice and in mice following bone marrow transplantation. Preliminary data indicate that thyroid hormones stimulate B lymphopoiesis in long-term bone marrow cultures and that B lineage cells express the thyroid hormone receptor (TR). Experiments in Aim 2 will determine which of the multiple TR isoforms are expressing developing B lineage cells, and subsequent studies will examine the functional effects of thyroid hormones on those populations. Potential effects of thyroid hormones on cells of the hematopoietic microenvironment will also be assessed. There has been considerable speculation in the literature that additional hormones that include anterior pituitary gland derived Prolactin and Growth Hormone as well as Insulin-Like Growth Factor-I play a role in B cell development. Whether or not these hormones are required for B lymphopoiesis will be addressed in Aim 3. B cell development will be examined in knockout and naturally occurring genetic mutant mice in which the production of one or more of these hormones is deficient. The mechanism of action of the hormone(s) identified as being necessary for B cell development will then be evaluated in vitro. Taken together, these studies will define the role of extramedullary signals during B cell development and offer the promise for successful intervention in immune deficiencies.